Oxygenated triterpenoid acid derivatives



United States Patent 3,140,301 OXYGENATED TRITERPENOID ACID DERIVATIVES Josef Fried, Princeton, N.J., assignor to Olin Mathieson Chemical Corporation, New York, N.Y., a corporation of Virginia No Drawing. Filed Apr. 19, 1962, Ser. No. 188,900 14 Claims. (Cl. 260-3973) This invention relates to, and has as its objects the provision of new, physiologically active steroids, methods for their production and new intermediates useful in said preparation.

The final products of this invention may be represented by the following formula wherein Z is selected from the group consisting of hydrogen, hydroxy and acyloxy; Y is selected from the group consisting of hydrogen, hydroxy, acyloxy and 0x0 (0:); and R and R may be the same or different and are selected from the group consisting of hydrogen, hydroxy and acyloxy. (Whenever in this application, and the claims appended hereto, a curved line (i) is employed in the linkage of atoms in any of the formulae set forth herein, it is meant to denote that the connected atom may be either in the alpha or beta position as is determined in the respective compounds involved.)

The preferred acyloxy radicals are those of hydrocarbon carboxylic acids of less than twelve carbon atoms, for example, the lower alkanoic acids (e.g., acetic, propionic, butyric and tert-pentanoic acids), the lower alkenoic acids, the monocyclic aryl lower alkanoic acids (e.g., phenacetic and fl-phenylpropionic acid), the cycloalkane carboxylic acids, and the cycloalkene carboxylic acids.

The final products of this invention which are unsubstituted in the 2l-position (i.e., where Z is hydrogen) are physiologically active compounds which possess progestational activity and thus may be employed in place of progesterone in the treatment of habitual abortion. Administration can be accomplished in the same manner as progesterone, for example, the dosage being adjusted for the relative potency of the particular steroid. Those final products of this invention which are oxygenated in the 21- position (i.e., Z is hydroxy or acyloxy) are physiologically active compounds which possess mineralocorticoid activity and thus can be employed instead of desoxycorticosterone in the treatment of Addisons disease, for which purpose they may be administered in the same manner as desoxycorticosterone.

The final products of this invention are prepared by the process of this invention which entails a number of steps beginning with a (triterpenoid acid) as the starting ma- 3,140,301 Patented July 7, 1964 ice terial. By a triterpenoid acid, it is here meant a polymethyl steroid having a D ring structure represented by the following formula Ebnricoic Acid uogl v RIIOACI (II) R"=CH C O (III) R"O=CH OO RIIO Ci I (IV) R"=CH C O (V) R=CH:CO

R OHJg K OHgOR CH OR' CH OR r5 egg;

The final products of this invention, wherein Z is hydrogen, are prepared by a process of this invention which entails a number of steps beginning with corresponding 21- hy-droxy steroid derivatives as starting materials. These steps are shown by the following equations, wherein Y is hydroxy, acyloxy or 0x0 (0:), and A is lower alkyl or tolyl:

OHgOH (XVI) Y=CH3COO CH OSOrA C HzI (XIX) Y=CH3O 0 0 (XVIII) Y=C H 0 0 (Q) (XX) Y=CH C 0o (XXI) Y=OH (XXII) Y=CHsG o 0 (XXIII) Y=O= In the first step of this invention the triterpenoid acid (e.g., eburicoic acid in the foregoing equations) is con verted to its 3-ester derivative (Compounds A). The 3- acetate of eburicoic acid is a known compound. Other 3-esters can be prepared in the usual manner by reaction with the desired acylating agent (e.g., acyl chloride or acid anhydride) in the presence of a base, such as pyridine. The preferred esters are those with hydrocarbon carboxylic acids of less than twelve carbon atoms, which may be formed by reacting with the acyl chloride or acid anhydride of a hydrocarbon carboxylic acid of less than twelve carbon atoms, such as one of the acids hereinbefore set forth.

The 3-ester is then converted to a corresponding ester of 3 hydroxy 24-keto-A -lanostene-2l-oic acid (Compound B). This may be accomplished by ozonolysis of Compounds A and reducing the ozonide formed by treatment with either hydrogen in the presence of a hydrogenation catalyst, e.g., palladium on charcoal, or an electropositive metal, e.g., zinc, in the presence of an acid, e.g., glacial acetic acid.

Compounds B are then lactonized by treatment with an acid anhydride and a salt of a strong base and a weak acid, such as sodium acetate in acetic anhydride, to yield a mixture of the a-lactone (Compounds D) and ,B-lactone (Compounds E of the corresponding 3-esters of 3B-hydroxy-24-keto-A -lanostene 21oic acid. The reaction is preferably carried out at an elevated temperature, such as the reflux temperature of the organic solvent employed and the two lactones are separated chromatographically. However, since both the oc-lflCtOHB and fl-lactone give the same product in the next step of the process, such separation is not necessary and a mixture of the lactones may be used directly.

Compounds C and D are then dehydrogenated, as by treatment with palladium on charcoal at an elevated temperature, to yield the corresponding 3-ester of 318,24-dihydroxy A lanostadiene 21 oic acid lactone (Compounds E).

Compounds E are then reduced by treatment with lithium aluminum hydride to yield the corresponding 343,21- dihydroxy A lanostatn'ene derivatives (Compounds F) Compounds F are then oxidized as by treatment with ozone and reduction of the ozonide formed, to yield 318, 21 dihydroxy 4,4,14a-trimethyl-A -5a-pregnene-20-one (Compounds G).

Compounds G are then oxidized as by treatment with chromium trioxide in glacial acetic acid to produce the 7,11,20-triketone (Compounds H), which are new compounds of this invention.

Compounds H of this invention are then treated with zinc and acetic acid to produce the pregnane-7-1l,20- triketones (Compounds J), which are substituted in the 2l-position, and which are also new compounds of this invention.

When a 3-ester compound is formed, it may be saponified in the usual manner, as by treatment with a base such as potassium hydroxide to yield the corresponding free 3/8-hydroxy derivative, and the free 3-hydroxy compound oxidized to the corresponding 4-keto derivative in the usual manner, as by treatment with chromium trioxide (Compounds K).

If a 2l-unsubstituted compound is desired, a compound containing a free ZI-hydroxy group (Compounds L) is acylated by treatment with an organic sulfonyl chloride, such as a lower alkanesulfonyl chloride (e.g., mesyl chloride) or tosyl chloride, to yield the corresponding 2l-sulfonic acid ester (Compounds L).

The 2l-sulfonic acid esters are then converted to their corresponding 21-iodo derivatives (Compounds M) by treatment with an alkali metal iodide (e.g., sodium iodide) preferably at an elevated temperature.

The 21-iodo derivatives are then reduced, as by treatment with sodium bisulfite to produce 2l-unsubstituted compounds (Compounds N). These compounds are then oxidized as by treatment with chromium trioxide in glacial acetic acid to produce the 7,11,20-triketone which are new compounds of this invention (Compounds P).

The triketones are then treated with zinc and acetic acid to produce the pregnane-7,11,20-triones, which are new compounds of this invention. When a 3-hydroxy or 3-acyloxy derivative is formed, it may be oxidized to the corresponding 3-keto derivative (after saponification of the 3-ester group, if present) to yield the final 3,-keto compounds of this invention (Compounds Q).

Like results as obtained above, with eburicoic acid as the starting material, may also be produced where the same procedure as set forth above is followed, but elemolic, pinicolic, polyporenic or tumulosic acid is substituted for eburicoic acid as the starting material.

The following examples illustrate the invention (all temperatures being in centigrade):

EXAMPLE 1 3 8,21 -Diacet0xy-4,4,14a-TrimethyZ-A -Sa-Pregnene ZO-One A. Eburicoic acid 3-acerate (I) .To a solution of 10 g. of eburicoic acid in 50 ml. of anhydrous pyridine is added 10 ml. of acetic anhydride and the mixture is allowed to remain at room temperature for 18 hours. Five grams of ice are then added and 30 minutes later the mixture is diluted slowly with 250 ml. of ice and water. The resulting precipitate is filtered, washed thoroughly with water, dried in vacuo and recrystallized from 95% alcohol yielding pure eburicoic acid 3-acetate.

Similarly, by substituting other acid anhydrides of acyl halides for the propionic anhydride in the procedure of Example 1, the corresponding 3-esters are formed. Thus, butyric anhydride and benzoyl chloride yield the 3-butyrate and 3-benzoate of eburicoic acid, respectively.

Similarly, treating 10 g. of tumulosic acid according to the procedures set forth in part A, tumulosic acid 3,16- diacetate is obtained.

B. 3,8-acetxy-24-keto-M-lanostene-ZI-0ic acid (ll).- Through a solution of 15 g. of eburicoic acid 3-acetate (I) in a mixture of 150 ml. of chloroform and 150 ml. of ethyl acetate, cooled in a Dry Ice-acetone bath, is passed 26.2 1. of ozone (1 mole of ozone contained in .89 1. of oxygen). The resulting solution is allowed to warm to room temperature and then added to a suspension of 975 mg. of pre-reduced palladium on charcoal catalyst in 50 ml. of ethyl acetate. 550 ml. of hydrogen is taken up rapidly, following which the solution is filtered and the filtrate evaporated to dryness in vacuo.

Alternately the ozonide can be decomposed with zinc in acetic acid as follows: The ozonolysis mixture obtained from 50 g. of eburicoic acid 3-acetate in 50 ml. of chloroform and 500 ml. of ethyl acetate, is allowed to warm up to when it is diluted with 50 ml. of glacial acetic acid. Powdered zinc is then added in portions with stirring and the temperature allowed to rise to A total of g. of zinc is required. After 2% hours the reaction mixture is filtered and the zinc and zinc salts washed thoroughly with ethyl acetate. The ethyl acetatechloroform filtrate is washed thoroughly with water, dried over sodium sulfate and evaporated to dryness in vacuo. A total of about 56 g. of the crude keto acid IV is obtained.

The acid (II) is obtained in pure form by chromatography on neutral alumina. For this purpose a solution of 14 g. of the crude acid is dissolved in 50 ml. of benzene and charged to the column containing 280 g. of alumina. 50% chloroform benzene (9 l.) elutes about 1.9 g. of pure acid melting at about 234236, which is followed by about 1.2 g. of acid when the eluent is changed to 75% chloroform in benzene (3 1.). An additional 1.3 g. of pure acid is obtained with chloroform (5 1.). The column is then stripped with 5% acetic acid in chloroform (2 l.) which elutes about 10.4 g. of crude material which is dissolved in 100 ml. of benzene and rechromatographed on 200 g. of silica gel. Elution with benzene (750 ml.) gives about 4 g. of amorphous material which is followed by crystalline acid (about 2.4 g.) when the eluent is changed to chloroform (8 1.). The pure acid (II) has the following properties:

M.P. 236238; [a] +52 (0., .49111 chlf.); x3 2; 5.78 and 5.90 3E3? 5.83-5.90, 8.05, 9.76 and 9.94 1.

Analysis.-Calcd. for C H O (514.72): C, 74.67; H, 9.79. Found: C, 74.64; H, 9.54.

Similarly, tumulosic acid 3,16 diacetate may be treated in accordance with the procedure set forth in Part B above, yielding 3 5,160: diacetoxy 24 keto-A -lanostene-21-oic acid.

C. 313 acetoxy 24 hydroxy A 7 lanostadiene- 21-0ic acid lactone (or-lactone) (III) and 3fl-acet0xy-24- hydroxy-A -lan0stadiene-21-0ic acid lactone (ti-lactone) (I V).-To a solution of 15.4 g. of 3B-acetoxy-24-keto-A lanostene-Zl-oic acid (II) in 150 ml. of acetic anhydride is added 3.75 g. of anhydrous sodium acetate and the resulting suspension is heated under reflux for 10 hours. Upon cooling, the acetic anhydride solution is decanted from the sodium acetate and the latter washed thoroughly with benzene. The combined acetic anhydride-benzene solutions are evaporated to dryness in vacuo, the residue redissolved in benzene and filtered from the precipitated sodium acetate. The clear benzene solution is evaporated 8 to dryness leaving a mixture of the aand B-enol lactones (III and IV) (about 15.1 g.). Separation is achieved by chromatography on neutral alumina as follows: The total residue is dissolved in 50 ml. of benzene and 50 ml. of hexane and charged to a column containing 300 g. of neutral alumina. Elution with 250 ml. of benzene-hexane (1:1) produces about 3.1 g. of crude crystalline 3fl-acetoxy-24-hydroxy-A -lanostadiene-21-oic acid is lactone (ix-lactone) (III), which after crystallization from ethanol is analytically pure .and has the following properties:

M.P. about 169171; [a] |-37; 322i? 5.69, 5.78, 5.93

(weak), 8.05, 12.05, 12.62 and 13.30

The 12.05 and 12.63 band are diagnostic for the a-lactone and are absent in the fi-lactone.

Analysis.Calcd. for C H O (496.): C, 77.37; H, 9.73. Found: C, 77.41; H, 9.82.

Continued elution of the alumina column with benzene (8 1.) produces a total of about 4 g. of material in 12 fractions, all of which melt between 160 and represent a mixture of the aand ,B-lactones. Rechromatography of this mixture is necessary to obtain the pure 8- lactone. For the purpose all of the fractions are combined (4 g.). dissolved in 20 ml. of benzene and 80 ml. of hexane and charged to a column of 120 g. of neutral alumina. Elution with benzene-hexane (1:4) produces, in the first 500 ml., about 827 mg. of the pure a-lactone (III) which is followed by elution with the same solvent mixture (5.5 l.) and on elution with benzene-hexane (1:1, 2 l.) by a total of about 2.9 g. of material, representing a mixture of 01.- and B-lactone melting at about 158-160. Continued elution of the column with benzene (9 1.) yields a total of about 1.2 g. of material which after recrystallization ethanol constitutes pure 3fi-acetoxy-24-hydroxy-A lanostadiene-21-oic acid lactone (fi-lactone) (IV) (about 404 mg.) possessing the following properties:

M.P. about 190-191"; [a] +64.,- (c. .87 in chlf.); E31? 5.70, 5.79, 5.97 (weak), 8.08, 11.50, 11.50, 11.80 and 13.50

The 11.80 r band is absent in the a-lactone.

Analysis.-Calcd. for C H O (496.70): C, 77.37; H,

9.73. Found: C, 77.56; H, 9.73.

Similarly, treating the 319,16a-diacetoXy-24-keto-A lanostene-Zl-oic acid obtained in part B, in accordance with the procedures set forth in part C, yields 35,16a-diacetoxy-24-keto A -lanostadiene-2l-oic acid lactone (oz-lactone) and 95,16tx-diacetoxy-24-hydroxy-A -24-lanostene-21-oic acid lactone S-lactone).

D. 373 acctoxy 24 hydroxy A812(22),23 lanostatriene-21-0ic acid lactone (a-pyrone) (V).A suspension of 180 mg. of 10% palladium on charcoal in 25 ml. of p-cymene is distilled until approximately 3 ml. of solvent have been removed. The final temperature of the vapors is over 250 mg. of the thoroughly dried aenol lactone (III) is then added and the resulting suspension heated under reflux with stirring for 2 hours under a blanket of nitrogen. The mixture is cooled, filtered and the solvent removed in vacuo. The residual crystalline material on recrystallization from absolute ethanol furnishes the pure ix-pyrone (V) in about 75% yield possessing the following properties:

M.P. about 228-2285 [a] 114 (chlf. M13, 305 mu (e=8,850); A232 5.79, 5.90, 6.11, 6.35, 8.95, 11.90 and 12.69;.

Analysis.Calcd. for C H O (494.68): C, 77.69; H, 9.37. Found: C, 77.77; H, 9.43.

When the fi-enol lactone (IV) is substituted for the alactone (III) in part D and the reaction time is prolonged to 6 hours, the pyrone (V) is obtained in about 60% yield.

Moreover, when a mixture of aand fl-enol lactones (III and IV) (80 g.) is dehydrogenated with 80 g. of 10% palladium on charcoal in 700 ml. of p-cymene for 9 6 hours, about 50 g. of the pure a-pyrone (V) of M.P. about 226228 is obtained.

Furthermore, if another ester of eburicoic acid, such as the 3-propionate, the 3-butyrate or the 3-benzoate is substituted for the S-acetate in the procedures of either part B or part C and the procedures of Examples 1 through 8 are carried out, the corresponding 3-esters are obtained.

Similarly, treating the 3fi,16a-diacetoxy lactones obtained in part C, in accordance with the procedures set forth in part D above, yields 3,3,16a-dlfl66tOXY-Z4-hY- droxy A lanostatriene 21 oic acid lactone (ocpyrone).

E. 313,21-dihydrxy-A -lanostatriene (VI) .A solution of g. of the a-pyrone (V) in 210 ml. of freshly distilled tetrahydrofuran is added over a 15-minute period to a refluxing solution of 5 g. of lithium aluminum hydride in 125 ml. of tetrahydrofuran with stirring under a blanket of nitrogen. Reflux is continued for an additional 2 hours and the solution is cooled to room temperature. Saturated sodium sulfate solution is then added carefully until all the lithium aluminum hydride is decomposed, after which the reaction mixture is shaken with several 200 ml. portions of benzene and the resulting extracts decanted from the inorganic salts until all the organic material is extracted. The benzene-tetrahydrofuran solution is dried over sodium sulfate and evaporated to dryness in vacuo. The resulting residue (about 4.6 g.) is dissolved in 100 ml. of benzene and the solution chromatographed on 100 g. of neutral alumina washing the column with 800 ml. of benzene to remove some impurities. The desired trienediol (V1) is obtained by elution with 2800 ml. of chloroform in benzene. The combined eluates are evaporated to dryness and recrystallized from ether, which results in about 2.06 of the pure trienediol (VI) possessing the following properties:

M.P. about 166168; [a] 68 (chit); 15.13,, 244 m (e =32,800); Milli? 3.10, 9.71 and 10.40,.

Analysis.-Calcd. for C H O (440.68): C, 81.76; H, 10.98'. Found: C, 81.63; H, 10.91.

Continued elution of the alumina column with chloroform (1.1) elutes about 200 mg. of crystalline material whic hafter recrystallization from acetone has the following properties:

M.P. about 199-200"; [a] 37 (0., .96 in chlf.); N23,, no selective absorption; A313? 3.00

Analysis.Calcd. for C H O (416.72): C, 78.20; H, 11.38. Found: C, 77.92, 78.25; H, 11.12, 11.33.

This compound represents 36,21,24 trihydroxy A lanostene.

Similarly, treating the 3 3,16a-diacetoxy-24-hydroxy- A -lanostatriene-2l-oic acid lactone (a-pyrone) obtained in Part D above, according to the procedures of Part E, yields 36,16oc,2l-trihydroxy-A -lanostatriene.

F. 38,21 -diacet0xy-A -lanostatriene (VII .A solution of 200 mg. of the triene (VI) in 2 ml. of anhydrous pyridine and 0.2 ml. of acetic anhydride is allowed to stand at room temperature overnight. Removal of the reagents in vacuo leaves a residue on crystallization from methanol furnishes the pure diacetate (VII) possessing the following properties:

M.P. about 131132 [a] +87 (ohlf.); X3}; 241 my. (6 =32,100) kg??? 5.74, 8.02, 8.19, 9.86;.

Analysis.--Calcd. for C H O (524.75): C, 77.82; H, 9.99. Found: C, 77.75; H, 10.01.

Similarly, if other acylating agents, such as propionic anhydride, butyric anhydride and benzoyl chloride, are substituted for the acetic anhydride in the procedure of Example 12, the corresponding diesters are formed. Similarly, treating the 3B,160,Z1-t1ii1YdI0XY-A lanostatriene obtained in part B above, according to the procedures set forth in part F, yields 3 ,8,16u,21-triacetoxy- [1 -1an'ostatriene.

G. 35,21-diacet0xy-4,4,I4u-trimethyl A -5a pregnene- 20-0ne (VIII) .-100 mg. of the trienediol diacetate (VII) is dissolved in 10 m1. of ethyl acetate and ozonized at 25 with 3 mole equivalents of ozone. To the resulting solution are added at room temperature a few drops of acetic acid and then portionwise a total of 1 g. of zinc dust until a negative starch iodide test is observed, which requires about 3 hours. The mixture is then filtered, washed with a saturated salt solution, dried over sodium sulfate and evaporated to dryness in vacuo. A crystalline residue (about 82 mg.) is obtained, which on recrystallization from methanol yields about 37 mg. of material melting at about 182184. Further crystallization from methanol furnishes analytical material possessing the following properties:

about 187188.5; [a] +101 (0., .22 in chlf.); R 5.73 (shoulder), 5.78, 8.03, 9.30, 9.70 and 9.88u.

max.

EXAMPLE 2 3 {3,21 -Diacet0xy-4,4,I 4a-Trz'methyl-A -5a-Pregnene- 7,11,20-Tri0ne (X) A solution of 23 mg. of 3,8,21-diacetoxy-4,4,14a-trimethyl-A 6a-pregnene-ZO-one (VIII) in 2 ml. of glacial acetic acid is maintained at a temperature of 77-78". Into this solution is slowly stirred a solution of 20 mg. of chromium tn'oxide in 1 ml. of glacial acetic acid over a 2*O-minute period. After allowing the stirred mixture to react for 25 minutes, it is cooled to room temperature, the bulk of the glacial acetic acid is removed in vacuo and the residue is taken up in water and chloroform. The chloroform extract is then washed three times with water, dried over sodium sulfate and the solvent removed in vacuo. Theresidue weighs 24 mg. and is readily crystallized from methanol to furnish 18 mg. of 35,21- diacetoxy 4,4,140: trimethyl A 5a-pregnene-7,l1,20- trione possessing the following properties:

M.P. 191192; [a] 107; (0., .59 in chlf.); MP 268 EXAMPLE 3 3 fl-A cetoxy-Z] -Hydr0xy-4,4,14u-Trimethyl-A -5a- Pregnene-7,11,20-Tri0ne (XII) To a solution of 25 mg. of 3fi,2l-diacetoxy-4,4,l4utrimethyl-A -5a-pregnene-7,11,20-trione (TX) in 20 ml. of methanol is stirred in under nitrogen, 0.2 ml. of 10% oxygen-free potassium carbonate. After storage at room temperature for 2 hours, 0.02 ml. of glacial acetic acid is added. After the addition of 10 ml. of water, the methanol is removed in vacuo. The mixture is then extracted with chloroform, the chloroform extract is washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The resulting crystalline residue after recrystallization from methanol furnishes 20 mg. of the pure 3fi-acetoxy-Z1-hydroxy-4,4,14a-trimethyl-A -5a-pregnene-1,1 1,20-trione (XII) Similarly, treating the 3/3,16a,21-triacetoxy-4,4,14atrimethyl-A -5a-pregnene-7,11,20-trione obtained in Example 2 according to the procedures set forth in Example 3 yields 3B,16a-diacetoxy-21-hydroxy-4,4,14a-trimethyl- A -5 u-pregnene-7, 1 1,20-trione.

I T. EXAMPLE 4 3fl-Acetoxy-4,4,1la-Trimethyl-A -5a-Pregnene- ZO-One (XIX) A. 3B-acet0xy-2I -hydrxy-4,4,14a-trimethyl-A a-pregrzene-ZO-orze (XVI).To a solution of 45 mg. of 35,21- diacetoxy-4,4,14tx-trimethyl-A -5a-pregnene-ZO-one (VIII) in 20 ml. of methanol is added with stirring under nitrogen .2 ml. of oxygen-free potassium carbonate. After 2 hours at room temperature .02 ml. of glacial acetic acid is added and after the addition of water the methanol is removed in vacuo. The mixture is extracted with chloroform, the chloroform extract washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The resulting crystalline residue after recrystallization from methanol furnishes about 34 mg. of the pure 3-monoacetate (XX) possessing the following properties: M.P. about 202204; [a] -}93 (0., .38 in chlf.)

Analysis.Calcd. for C H O (416.58): C, 74.96; H, 9.68. Found: C, 75.14; H, 9.64.

B. jfi-acetoxy 21 mesyl0xy-4,4,14a-trimethyl-A -5apregnene-ZO-one (X VI ).To a solution of 38 mg. of the 3fl-monoacetate (XVI) in 1 ml. of anhydrous pyridine is added at 0 .055 ml. of methanesulfonyl chloride in .5 ml. of chloroform. The reaction is allowed to remain at 0 for 2% hours, after which it is stopped by the additional of a small amount of ice. Chloroform and water are added and after separation of the phases the chloroform solution is washed with dilute sulfuric acid, water and then with dilute sodium bicarbonate keeping the extract cool at all times. The chloroform extract is dried over sodium sulfate, filtered and evaporated to dryness in vacuo leaving the 21-mesylate (XXIX) as a crystalline residue melting at about 109-110".

C. 3,8-aceloxy 21 iodo-4,4,14a-trimethyl-M-Sa-pregnene-ZO-one (XVIII).A solution of 47 mg. of the 21- mesylate (XVII) and 120 mg. of sodium iodide in 1.5 ml. of acetone is refluxed for 10 minutes on the steam bath. Water is added and the mixture is extracted with chloroform. The chloroform extract is washed with water, dried over sodium sulfate and the solvent removed in vacuo. The dry residue represents the 21-iodo Compound (XXXIII), M.P. about 146149 (blackening at about 185).

D. 3B-acetoxy-4,4,14a-trimethyl-M-Sa-pregnene-20-0ne (XIX ).To a solution of 47 mg. of the iodo compound (XVIII) in 1 ml. of dioxane is added .9 ml. of a 5% sodium bisulfate solution and the resulting mixture refluxed for 1 hour on the steam cone. Water and chloroform are added and after separation of the layers, the chloroform phase is washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. The residual crystalline material (about 25.5 mg.) on recrystallization from methanol furnishes the pure pregnene derivative (IX) possessing the following properties:

EXAMPLE 5 3 fl-A cet0xy-4,4,14a-Trimethyl-M-Su-Pregnene- 7,11,20-Tri0ne (XX) Following the procedure of Example 2 but substituting 25 mg. of 3 8-acetoxy-4,4,14a-trimethyI-A -Sa-pregnene- 20-one (XIX) for the 3,8,21-diacetoxy-4,4,14a-trimethyl- A -5a-pregnene-20-one (VIII), 3B-acetoxy-4,4,14a-trimethyl-A -5a-pregnene-7,11,2O-trione is obtained.

max.

12 Similarly, treating the 35,16a-diacetoxy-4,4,14a-trimethyl-A -5a-pregnene-ZO-one obtained in Example 4, according to the procedures set forth in Example 5 yields 3,8,160: diacetoxy-4,4,14a-trimethyl-A -5a-pregnene-7,11, 20-trione.

EXAMPLE 6 35,21-Diacet0xy-4,4,14a-Trimethyl-Sa-Pregnane- 7,11,20-Tri0ne (XI) 150 mg. of zinc dust is added portionwise, over a 15- minute period, to a solution of 50 mg. of 35,21-diacetoxy- 4,4,14a-trimethyl-A -5a-pregnene-7,11,20-trione (IX) in 4 ml. of glacial acetic acid maintained at 75-85". The solution is allowed to remain at that temperature for a total of 30 minutes, then cooled, filtered and the solution concentrated to a small volume. Water is added to the mixture which is then extracted with chloroform. The extract is successively washed with water, sodium carbonate and again with water. The Washed extract is then dried over sodium sulfate and evaporated to dryness in vacuo. The material is readily crystallized from methanol and consists of 3,6,2l-diacetoxy-4,4,14a-trimethyl-5apregnane-7,11,20-trione.

EXAMPLE 7 3-A cet0xy-4,4,14a-Trimethyl-5u-Pregnane-7,11,20- Trione (XXII) Following the procedure of Example 6, but substituting 40 mg. of 3fi-acetoxy-4,4,14a-trimethyl-A Saregnene-7, 11,20-trione for the 313,21-diacetoxy-4,4,14a-trimethyl- A -Sa-pregnene 7,11,20 trione, 3B-acetoxy-4,4,14u-trimethyl-5a-pregnane-7,l1,20-trione (XXII) is obtained.

Similarly, treating the 3B,16a-diacetoxy-4,4,14a-trimethyl-A -5a-pregnene-7,11,20-trione obtained in Example 5, Be, 16a-diacetoxy-4,4,14u-trimethyl-5a-pregnane- 7,11,20-trione is obtained.

EXAMPLE 8 3,21-Dihydr0xy-4,4,14a-Trimethyl-Sa-Pregnkme- 7,1],20-Tri0ne (X) A solution of mg. of the diacetate (IX) obtained in Example 6 in 14 ml. of oxygen free 1 N ethanolic KOH is allowed to stand at room temperature for 19 hours with the exclusion of air. At the end of this period, the solution is neutralized with 1 N sulfuric acid, diluted with H O, the ethanol removed in vacuo and the aqueous suspension extracted with C01 The CCl extract is dried over sodium sulfate and evaporated to dryness in vacuo. There remains a crystalline residue, which after recrystallization from acetone furnishes 313,21-dihydroxy- 4,4,14tx-trimethyl-5ot-pregnane-7,1 1,20-trione (X) EXAMPLE 1O .ifi-Hydroxy-ZI-A cetoxy-4,4,14a-Trimethyl-5a- 7,11,20-Tri0ne (XII) 100 mg. of the diol (X) obtained in Example 9 is monoacylated with 1 ml. of a solution containing 28 mg. of

acetic anhydride in pyridine (1.1 mole equivalent of acetic anhydride) at room temperature for 18 hours. The reagents are evaporated in vacuo and the crystalline resi- 13 due is recrystallized from methanol. After two crystallizations 3B hydroxy 21 acetoxy-4,4,l4u-trimethyl-5apregnane-7,11,20-trione (XII) is obtained.

EXAMPLE 11 21 A cetxy-4,4,]4a-TrimethyI-Su-Pregnane- 3,7,11,20-Tetra0ne (XV) A solution of 80 mg. of the 21-acetate obtained in Example in 8 ml. of acetone is oxidized with 1.0 ml. of a solution containing 20 mg. of chromium trioxide and 32 mg. of concentrated sulfuric acid per milliliter of 90% aqueous acetone. The reaction is allowed to proceed for minutes when excess chromium trioxide is decomposed by the addition of methanol. Water and chloroform are added and the chloroform extract washed with water, dried over sodium sulfate and evaporated to dryness, yielding 21-acetoxy-4,4,14a-trimethyl-5a-pregnane-3,7,11, ZO-tetraone.

EXAMPLE 12 21 -Hydr0xy-4,4,14a-Trimethyl-5a-Pregnane-3,7,11,20- Tetraone (XIV) Following the procedure of Example 3 but substituting 25 mg. of 2l-acetoxy-4,4,l4a-trimethyl-A -5rx-pregnene- 7,1 1,20-trione, 2l-hydroxy-4,4,14a-trimethyl-5a-pregnane- 3,7,11,20-tetraone is obtained.

EXAMPLE 13 3,8-Hydroxy-4,4,14m-Trimethyl-Sa-Pregnane-ZZ] ,20-

Trione (XXI) A solution of 100 mg. of the pregnane 3-acetate (XXI) in 4 m1. of oxygen-free 1 N ethanolic KOH is allowed to stand at room temperature for 19 hours with the exclusion of air. At the end of this period the solution is neutralized with l N sulfuric acid, diluted with water, the ethanol removed in vacuo and the aqueous suspension extracted with chloroform. The chloroform extract is dried over sodium sulfate and evaporated to dryness in vacuo. There remains a crystalline residue, which after recrystallization from acetone furnishes analytically pure 3,8 hydroxy 4,4,l4a trimethyl 5 a pregnane 7,11,20- trione (XXI).

EXAMPLE 14 4,4,14a-Trimethyl-5er-Pregnane-3,7,11,ZO-Tetraone (XXIII) To a solution of 80 mg. of the pregnane-S-ol (XXI) in 8 ml. of reagent grade acetone is added with stirring 1.0 ml. of a solution containing mg. of chromium trioxide and 32 mg. of sulfuric acid in 90% aqueous acetone. The reaction is allowed to proceed for 15 minutes after which time it is stopped by the addition of a few drops of 95% ethanol. Water is added and the steroid extracted with chloroform. The chloroform extract is dried over sodium sulfate and evaporated to dryness in vacuo. There remains a crystalline residue which, after recrystallization from acetone produces 4,4,l4rx-trimethyl- 5u-pregnane-3,7,1 1,20-tetraone (XXIII) EXAMPLE 15 3B,16oc,21 -Trz'acet0xy-4,4,14a-Trimethyl-A Pregnadiene-ZO-One Substituting polyporenic acid C for eburicoic acid and treating said polyporenic acid C according to the procedures set forth in Example 1, parts A through G yields, 3B,l6u,21 triacetoxy 4,4,14a trimethyl A7301) pregnadiene-ZO-one.

EXAMPLE 16 3,8,16a,21 -Triacet0xy-4,4,14a-Trimethyl-A -Pregnene- 7,11,20-Tri0ne Treating the 35,16a,21-triacetoxy 4,4,l4oc trimethyl- A -pregnadiene-20 obtained in Example 15, according to the procedures set forth in Example 2 yields 35,160, 21 triacetoxy 4,4,l4oc trimethyl A pregnene 7,11, 20-trione.

14 EXAMPLE 17 3 3,21 -Diacet0xy4,4,14a-Trimethyl-A -5a-Pregnene- 7,11,20-Trione (X) A. 35 acetoxy 24 hydroxy-A -lanostatriene- 21-0ic acid lact0ne.A solution of 5 g. of 3fl-acetoxy-24- hydroxy-A -lanostatriene-21oic acid lactone (V) in 350 ml. of glacial acetic acid is saturated with dry hydrogen chloride gas first at 10 and finally as more HCl dissolves at 0. This requires a total of 30 minutes. The solution is maintained for an additional hour at 0 and then evaporated to dryness in vacuo. The resulting crystalline residue on recrystallization from ethanol and chloroform furnishes about 3.75 g. (75%) of a mixture consisting largely of the A'- and some of the A isomer, M.P. 229-231; [Q 135 (chlf.). A sample of this product is chromatographed on acid-washed alumina using a :1 ratio of alumina to sample. After elution of the A -isomer with chloroform-benzene (1:8) the main fractice is eluted with pure chloroform to give the pure A' -isomer (1X), which on recrystallization from methanol has the following properties: M.P. 230Z30.-5; 144 (chlf.).

Analysis.Calcd. for C H O (494.68): C, 77.69; H, 9.37. Found: C, 77.92; H, 9.40.

B. 35,21 diacetoxy 4,4,14a trimethyl A 5oz pregnene-20-0ne.Treating the 3 B acetoxy 24 hydroxy- M -lanostatriene-2l-oic acid lacetone obtained in part A above, according to the procedures set forth in Example 1, parts E to G, yields 3/3,21-diacetoxy-4,4,14utrimethyl-A' -5a-pregnene-20-one.

C. 3&2] diacetoxy 4,4,14u trimethyl A 5a pregnene-7-J1,20-tri0ne (X) .Treating the 3,8,21-diacetoxy- 4,4,14u-trimethyl-A' -5a-pregnene-20-one obtained in part B above, according to the procedures set forth in Example 2, yields 3B,21-diacet0xy-4,4,14a-trimethyl-A -5a-pregene- 7 1 1 ,20-trione.

The invention may otherwise be variously embodied within the scope of the appended claims.

What I claim is:

1. A compound having the formula rg. W QQF wherein Z is selected from the group consisting of hydrogen, hydroxy and the acyloxy radical of a hydrocarbon carboxylic acid of less than twelve carbon atoms; Y is selected from the group consisting of hydoxy, oxo and the acyloxy radical of a hydrocarbon carboxylic acid of less than twelve carbon atoms; and each R and R is selected from the group consisting of hydrogen, hydroxy, and the acyloxy radical of a hydrocarbon carboxylic acid of less than twelve carbon atoms.

3. 3,21-diacet0Xy-4,4,14-trimethyl-5a-pregnane-7, 1 1,20- trione.

4. 3 acetoxy 21 hydroxy-4,4,l4-trimethyl-5a-pregname-7,1 1,20-trione.

5. 3 -acet0xy 4,4,14 trimethy1-5a-pregnane-1,l1,20- trione.

6. 3,2,1 diacetoxy 4,4,14-trimethyl-A -Sa-pregnene- 7,11,20-trione.

7. 21 hydroxy 4,4,14a-trimethyl-Sa-pregnane-3,7,11, ZO-tetraone.

8. 3,8 hydroxy 4,4,14a-trimethyl-a-pregnane-7,ll, 20-trione.

9. 4,4, 140c-tli1116tl1Y1-5 oc-prcgnane-3,7, 1 1,20-tetraone.

10. 21 *acetoxy 4,4,14a trimethyl c pregnanc- 3,7,11,20-tetraone.

1'1. 3fl,16oc,21 triacetoxy 4,4,14a trimethyl-A -pregnene-7,1 1,20-trione.

12. 3,21 dihydroxy 4,4,14zx trimethyl 5a pregname-7,11,20-trione.

13. 3,3 hydroxy 21 acetoxy 4,4,14oc trimethyl- 5a-pregnane-7,11,20-trione.

14. 3fi,16oc,21 triacetoxy 4,4,14a-trin1ethyl-A pregnadiene-20-one.

Chamberlin et aL: Jour. Amer. Chem. Soc. (1953), p. 3477.

Elks: Jour. Chem. Soc. (1954), page 451.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No, 3,140,301 July 7, 1964 Josef Fried It is hereby certified that error appears in the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 6, line 30, for "4-keto read 3-keto column 8, line 17, for "C H O read C H O, line 48, for "9B 16 read 3B 16a column 9, line 43, for "whic hafter" read which after line 64, for "241 mu" read 242 mu column 10, line 70, for "l,l1,20-=trione" read 7, ll,20-trione column 12, lines 68 and 69, for "5 -7,ll,20-Tri0ne", in

italics, read 5qpregnane-7,ll,20Trione in italics; column 14, line 27, for "lacetone" read lactone column 15, line 4, for "hydoxy" read hydroxy line 14, for "-1,1l,20-" read 7 11,20-

Signed and sealed this 30th day of March 1965., (SEAL) Attcst:

ERNEST W. SWIDER EDWARD J. BRENNER Aitcsting Officer Commissioner of Patents 

1. A COMPOUND HAVING THE FORMULA 